High Throughput Screening Technology for Allosteric Kinase Inhibitors

描述（由申请人提供）：蛋白激酶在许多信号通路中发挥核心作用，是细胞功能的关键效应器。蛋白激酶活性的异常，无论是由于酶水平的改变还是由于激酶结构的突变，都是导致病理的原因。因此，蛋白激酶抑制剂可以作为治疗多种疾病的潜在药物，包括癌症、中枢神经系统疾病和炎症。药物发现工作主要是确定与ATP结合直接竞争的小分子配体。然而，通过结合高度保守的ATP位点来抑制一种激酶的分子往往会抑制其他激酶，从而导致潜在的药物安全性问题。将药物靶向到非活性构象的方法可以提供识别选择性抑制剂的手段。问题是没有很多方法可以检测蛋白激酶的非活性构象，而且没有一种方法可以很容易地用于药物发现。Encode Bio开发了一种光学技术，可用于鉴定蛋白激酶的变构调节因子，稳定蛋白激酶的非活性构象。我们建议在开发药物发现方法方面实现下一个关键的技术飞跃，通过生成一个系统来大量生产所需的assa试剂，以用于大型化学文库的高通量筛选。公共卫生相关性：蛋白激酶在调节大多数细胞功能中发挥重要作用。我们将开发具有通用效用的新型高通量测定方法，以鉴定在atp结合位点外结合的蛋白激酶抑制剂。这些检测可用于加速许多疾病治疗方法的开发，包括癌症、中枢神经系统疾病和炎症。我们将加速开发具有更好选择性和安全性的变构激酶抑制剂。

DESCRIPTION (provided by applicant): Protein kinases play a central role in many signaling pathways and are key effectors of cellular functions. Abnormalities in protein kinase activity, either due to changes in enzyme levels or mutations in the kinase structure, are responsible for pathologies. As such, protein kinases inhibitors can potentially be developed as therapeutics for many diseases, including cancer, central nervous system disorders and inflammation. Drug discovery efforts have primarily identified small molecule ligands that compete directly with ATP binding. However, molecules that inhibit one kinase by binding at the highly conserved ATP site often inhibit other kinases, resulting in potential drug safety issues. Approaches to target drugs to the inactive conformation may provide the means to identify selective inhibitors. The problem is that there are not many ways to detect the inactive conformation of protein kinases and none that can be easily employed for drug discovery. Encode Bio has developed an optical technology which can be employed to identify allosteric regulators of protein kinases that stabilize the inactive conformation of protein kinases. We propose to make the next critical technological jump in developing the approach for drug discovery by generating a system to mass produce the requisite assa reagents in quantities needed for high throughput screening of large chemical libraries. PUBLIC HEALTH RELEVANCE: Protein kinases play important roles in regulating most cellular functions. We will develop novel high throughput assays with universal utility to identify protein kinase inhibitors that bind outside the ATP-binding site. These assays could be used to accelerate the development of therapeutics for many diseases, including cancer, central nervous system disorders and inflammation. We will accelerate development of allosteric kinase inhibitors with potentially better selectivity and safety profiles.